Prenylation, the introduction of a farnesyl or geranylgeranyl moiety onto the sulfhydryl group of certain proteins, is an important post-translational modification central to many cellular processes. The enzymes responsible for these prenylations include the protein farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase). Prenylation may be required to give a protein sufficient hydrophobicity for translocation to the plasma membrane. Many proteins that undergo prenylation are critical to signal transduction pathways, and therefore cell membrane localization is essential for these proteins to operate properly (see, for example, Hurwitz, H. I.; Casey, P. J. Prenylation of CaaX-type proteins: Basic principles through clinical applications, in Curr. Top. Membr. 2002, 52, 531-550; and Gibbs, R. A.; Zahn, T. J.; Sebolt-Leopold, J. S. Non-peptidic prenyltransferase inhibitors: Diverse structural classes and surprising anti-cancer mechanisms, in Curr. Med. Chem. 2001, 8, 1437-1465).
One such signal transduction protein that requires farnesylation in order to function properly is Ras (see, Jackson, J. H.; Cochrane, C. G.; Bourne, J. R.; Solski, P. A.; Buss, J. E.; Der, C. J. Farnesol modification of kirsten-ras exon 4B protein is essential for transformation, in Proc. Natl. Acad. Sci. 1990, 87, 3042-3046). Because mutated Ras proteins that are constitutively activated are seen in a significant number of cancers, there is a great deal of interest in preventing Ras membrane localization. One way to prevent Ras membrane localization is to inhibit FTase, the enzyme responsible for farnesylating Ras (see, for example, Ayllon, V.; Rebollo, A. Ras-induced Cellular Events (Review), in Mol. Mem. Biol. 2000, 17, 65-73). Significant research efforts have been directed towards developing FTase inhibitors that mimic farnesyl pyrophosphate, which is the natural substrate for the enzyme (see, Gibbs, R. A.; Zahn, T. J.; Sebolt-Leopold, J. S. Non-peptidic prenyltransferase inhibitors: Diverse structural classes and surprising anti-cancer mechanisms, in Curr. Med. Chem. 2001, 8, 1437-1465). Indeed, the pyrophosphates of 3-allylfarnesol and 3-t-butylfarnesol have been shown to be nanomolar inhibitors of FTase, and the pyrophosphate of 3-(3,3-dimethylallyl)farnesol is a novel protein-selective inhibitor of this enzyme. These phosphate-substituted compounds are highly charged, however, and it is unlikely that they will be capable of traversing the cell membrane and entering the cell.
It has been discovered that the intracellular delivery of monophosphate analogs of such inhibitors may provide an effective therapeutic approach to treating diseases that are responsive to the inhibition of prenylation.